Aim 1. To quantify DA release in vivo and then assess whether DA release in patients with SCZ differs from that of healthy normal subjects. Progress in Aim 1. We attempt to simulate the DA release that they may be initiated by a number of environmental or other stimuli, as hypothesized by Grace and others. Recently, studies by Laruelle et al. have suggested a significant increase in DA release on average in SCZ as compared with normal controls using SPECT. We employed the same amphetamine dose as Laruelle, but our studies differ in 2 ways. First, ours is a bolus rather than continuous infusion method using PET and [11C]raclopride. Second, because of the design of some of our studies (See specific Aim 2 below) the DA release may also be augmented by low specific activity raclopride. Using several different methods involving a radioactive plasma input function and kinetic models or simple time activity curves, we observed a similar trend to that of Laruelle trend of elevated DA release, Figure 1, although not as marked. In schizophrenic subjects for whom we were able to perform 4 scans including low specific activity raclopride, there appears to be a trend for a greater difference in the dopamine surge compared to normals. The average % DA release is numerically larger for schizophrenic patients but the sample size and variance is still too great to reach any conclusions. Additional refinement, subtyping or analyses and more subjects are needed. We have also tried to maximize our ability to detect the difference between patients with SCZ and normals by modifying the timing of the bolus IV AMP given relative to the IV bolus [11C]raclopride. Figure 2 of some preliminary analyses below suggests that 5 minutes prior to radiotracer may be the optimal time for amphetamine administration. Aim 2. To measure the effect of DAe and the DA surge on the quantitation of DA receptor density using NMSP and RAC. Using amphetamine (AMP) and reserpine (RES), which, respectively, increases or decreases DAe, we will perturb the DA system. We will then measure the effects of these perturbations on DA D2 receptors ("D2-like"). Progress in Aim 2. This Aim is to examine the effects of endogenous dopamine on the quantification of absolute receptor density Bmax with [11C]raclopride and [11C]NMSP. To date, we have successfully completed eight normal subjects and four schizophrenic patients with two measurements of Bmax without and with amphetamine. Since each Bmax measurement requires both high and low specific activity [11C]raclopride, each subject received four PET scans over a period of 1-2 weeks. This is logistically a complex procedure, since in the case of the patients, they must remain drug-free between the pairs of PET scans, each pair of which are carried out on a single day. This has often required hospitalization in the Clinical Research Unit at Johns Hopkins. In some cases, for clinical reasons, it has been necessary to enter subjects into a two PET scan protocol only, with two high specific activity [11C]raclopride studies without and with amphetamine during the same day. This has occurred in one of the six patients recruited so far.